Do Individual and Neighborhood Characteristics Influence Perceived Air Quality?
Background: Despite improvements, air pollution still remains a major public health issue. Numerous epidemiological studies have demonstrated the adverse health effects of air pollution exposure based on modeled measures, but only a few have considered the health impact of perceived air quality. Improving our knowledge of individual perceptions is crucial to defining targeted actions and promoting appropriate intervention measures. Our objective is to investigate the relationship between subjective and objective measures of air pollution and to focus on how individual characteristics combined with the neighborhood socioeconomic deprivation index, measured at a fine spatial scale, may or may not alter this relationship. Materials and Methods: The subjective measures of air quality reported by a sample of Lyon residents were collected via an individual questionnaire. The objective measures of air pollution were modeled by the local air quality monitoring network of the Rhône-Alpes region at census block level. We used a socioeconomic deprivation index to capture the different socioeconomic dimensions at census block level. The statistical analysis was structured in two steps: (1) identification of individual determinants of the subjective measures of air quality using multiple correspondence analysis followed by hierarchical clustering; (2) identification of individual and contextual characteristics that may alter the relationship between the objective and subjective measures of air pollution. Results: Among the youngest and the middle aged population (ages 30 to 59), consistent results between level of satisfaction, perceived air quality and objective measures of air pollution were found whatever the individual characteristics of the population. It is less clear among the oldest population: globally no significant difference between the NO₂ concentrations and the level of satisfaction was observed. Conclusions: We found a significant relationship between the subjective and objective measures of air pollution in many population sub-groups with different combinations of individual characteristics. The relationship is less clear among the oldest population, which confirms previous findings. Our finding highlights that age combined with low level of education and unemployment, or women or health problems as well as the neighborhood deprivation index influence the level of air quality satisfaction.


Science is 1% inspiration and 99% biomarkers.
Neurodegeneration plays a key role in multiple sclerosis (MS) contributing to long-term disability in patients. The prognosis is, however, unpredictable coloured by complex disease mechanisms which can only be clearly appreciated using biomarkers specific to pathobiology of the underlying process. Here, we describe six promising neurodegenerative biomarkers in MS (neurofilament proteins, neurofilament antibodies, tau, N-acetylaspartate, chitinase and chitinase-like proteins and osteopontin), critically evaluating the evidence using a modified Bradford Hill criteria.


The Usefulness of Serological Inflammatory Markers in Patients with Rotator Cuff Disease-A Systematic Review.
Background and Objectives: Rotator cuff disease (RCD) is a prominent musculoskeletal pain condition that spans a variety of pathologies. The etiology and precise diagnostic criteria of this condition remain unclear. The current practice of investigating the biochemical status of RCD is by conducting biopsy studies but their invasiveness is a major limitation. Recent biochemical studies on RCD demonstrate the potential application of serological tests for evaluating the disease which may benefit future clinical applications and research. This systematic review is to summarize the results of available studies on serological biochemical investigations in patients with RCD. Methods: An electronic search on databases PubMed and Virtual Health Library was conducted from inception to 1 September 2021. The inclusion criteria were case-control, cross-sectional, and cohort studies with serological biochemical investigations on humans with RCD. Methodological quality was assessed using the Study Quality Assessment Tool for Observational Cohort and Cross-sectional studies from the National Heart, Lung, and Blood Institute. Results: A total of 6008 records were found in the databases; of these, 163 full-text studies were checked for inclusion and exclusion criteria. Nine eligible studies involving 984 subjects with RCD emerged from this systematic review. The quality of the studies found ranged from poor to moderate. In summarizing all the studies, several fatty acids, nonprotein nitrogen, interleukin-1 β, interleukin-8, and vascular endothelial growth factor were found to be significantly higher in blood samples of patients with RCD than with control group patients, while Omega-3 Intex, vitamin B12, vitamin D, phosphorus, interleukin-10, and angiogenin were observed to be significantly lower. Conclusions: This is the first systematic review to summarize current serological studies in patients with RCD. Results of the studies reflect several systemic physiological changes in patients with RCD, which may prove helpful to better understand the complex pathology of RCD. In addition, the results also indicate the possibility of using serological tests in order to evaluate RCD; however, further longitudinal studies are required.


Analysis of the presence and abundance of GABAA receptors containing two different types of alpha subunits in murine brain using point-mutated alpha subunits.
Gamma-aminobutyric acid, type A (GABAA) receptors are pentameric proteins of which the majority is composed of two alpha subunits, two beta subunits and one gamma subunit. It is well documented that two different types of alpha subunits can exist in a singles GABAA receptor complex. However, information on the abundance of such GABAA receptors is rather limited. Here we tested whether mice containing the His to Arg point mutation in the alpha1, alpha2, or alpha3 subunit at positions 101, 101, and 126, respectively, which render the respective subunits insensitive to diazepam, would be suitable to analyze this issue. Immunodepletion studies indicated that the His to Arg point mutation solely rendered those GABAA receptors totally insensitive to diazepam binding that contain two mutated alpha subunits in the receptor complex, whereas receptors containing one mutated and one heterologous alpha subunit not carrying the mutation remained sensitive to diazepam binding. This feature permitted a quantitative analysis of native GABAA receptors containing heterologous alpha subunits by comparing the diazepam-insensitive binding sites in mutant mouse lines containing one mutated alpha subunit with those present in mouse lines containing two different mutated alpha subunits. The data indicate that the alpha1alpha1-containing receptors with 61% is the most abundant receptor subtype in brain, whereas the alpha1alpha2 (13%), alpha1alpha3 (15%), alpha2alpha2 (12%), alpha2alpha3 (2%), and alpha3alpha3 combinations (4%) are considerably less expressed. Only within the alpha1-containing receptor population does the combination of equal alpha subunits (84% alpha1alpha1, 7% alpha1alpha2, and 8% alpha1alpha3) prevail, whereas in the alpha2-containing receptor population (46% alpha2alpha2, 36% alpha2alpha1, and 19% alpha2alpha3) and particularly in the alpha3-containing receptor population (27% alpha3alpha3, 56% alpha3alpha1, and 19% alpha3alpha2), the receptors with two different types of alpha subunits predominate. This experimental approach provides the basis for a detailed analysis of the abundance of GABAA receptors containing heterologous alpha subunits on a brain regional level.


Hyperfunctional complement C3 promotes C5-dependent atypical hemolytic uremic syndrome in mice.
Atypical hemolytic uremic syndrome (aHUS) is frequently associated in humans with loss-of-function mutations in complement-regulating proteins or gain-of-function mutations in complement-activating proteins. Thus, aHUS provides an archetypal complement-mediated disease with which to model new therapeutic strategies and treatments. Herein, we show that, when transferred to mice, an aHUS-associated gain-of-function change (D1115N) to the complement-activation protein C3 results in aHUS. Homozygous C3 p.D1115N (C3KI) mice developed spontaneous chronic thrombotic microangiopathy together with hematuria, thrombocytopenia, elevated creatinine, and evidence of hemolysis. Mice with active disease had reduced plasma C3 with C3 fragment and C9 deposition within the kidney. Therapeutic blockade or genetic deletion of C5, a protein downstream of C3 in the complement cascade, protected homozygous C3KI mice from thrombotic microangiopathy and aHUS. Thus, our data provide in vivo modeling evidence that gain-of-function changes in complement C3 drive aHUS. They also show that long-term C5 deficiency is not accompanied by development of other renal complications (such as C3 glomerulopathy) despite sustained dysregulation of C3. Our results suggest that this preclinical model will allow testing of novel complement inhibitors with the aim of developing precisely targeted therapeutics that could have application in many complement-mediated diseases.


Prevalence of shoulder pain in the community: the influence of case definition.
To compare estimates of the occurrence of shoulder pain according to (a) different approaches to defining 'shoulder' and (b) restricting the definition to only include those with associated disability. A postal questionnaire survey was sent to a sample of 500 patients registered with a general practice in south Manchester. After additional mailings to non-responders, 312 questionnaires were returned (66% adjusted response rate). Four definitions of shoulder pain were used to estimate the occurrence of symptoms derived from answers to the questionnaire. Two were based on questions asking directly about pain in the shoulder and the upper trunk and neck region respectively and two were based on markings on a pain drawing in the shoulder complex and the upper trunk respectively. To determine the occurrence of disabling shoulder pain responders were subsequently approached for interview. Of the responders, 232 (74%) were successfully interviewed. Those indicating that they were suffering from 'current' shoulder symptoms, pain on the day of interview, were asked to complete a short, 23 item, questionnaire enquiring about disability in daily living associated with such symptoms. In total 160 (51%) people reported shoulder pain according to at least one definition. This one month period prevalence ranged from 31% to 48% across the four definitions with the lowest estimate being for the question asking directly about shoulder symptoms. In total 84 people (27% of all respondents) answered positively to all four definitions. Only seven people who answered positively when asked directly about shoulder pain did not indicate symptoms on the pain drawing in the shoulder complex. By contrast 65 (30%) of those answering negatively to the direct question about shoulder pain indicated symptoms on the pain drawing in the upper trunk region or answered positively to the direct question about pain in the upper trunk or neck region. However only 19 (9%) of those answering negatively to the direct question indicated symptoms in the shoulder complex on the pain drawing, compared with 38 (18%) indicating symptoms in the upper trunk region and 59 (27%) symptoms in the upper trunk and neck region. Limiting the definition to only include current symptoms with some associated disability (at least one item on the disability questionnaire being answered positively) restricted the point prevalence to 20% (n = 46). Using a pain drawing based definition with case ascertainment restricted to an area in and around the shoulder complex is recommended for surveys assessing the occurrence of shoulder symptoms in the general population. To solve the problem of the poor specificity associated with symptom based definitions it is useful to incorporate an additional classification to restrict the definition to more disabling problems.


Inherited copper transport disorders: biochemical mechanisms, diagnosis, and treatment.
Copper is an essential trace element required by all living organisms. Excess amounts of copper, however, results in cellular damage. Disruptions to normal copper homeostasis are hallmarks of three genetic disorders: Menkes disease, occipital horn syndrome, and Wilson's disease. Menkes disease and occipital horn syndrome are characterized by copper deficiency. Typical features of Menkes disease result from low copper-dependent enzyme activity. Standard treatment involves parenteral administration of copper-histidine. If treatment is initiated before 2 months of age, neurodegeneration can be prevented, while delayed treatment is utterly ineffective. Thus, neonatal mass screening should be implemented. Meanwhile, connective tissue disorders cannot be improved by copper-histidine treatment. Combination therapy with copper-histidine injections and oral administration of disulfiram is being investigated. Occipital horn syndrome characterized by connective tissue abnormalities is the mildest form of Menkes disease. Treatment has not been conducted for this syndrome. Wilson's disease is characterized by copper toxicity that typically affects the hepatic and nervous systems severely. Various other symptoms are observed as well, yet its early diagnosis is sometimes difficult. Chelating agents and zinc are effective treatments, but are inefficient in most patients with fulminant hepatic failure. In addition, some patients with neurological Wilson's disease worsen or show poor response to chelating agents. Since early treatment is critical, a screening system for Wilson's disease should be implemented in infants. Patients with Wilson's disease may be at risk of developing hepatocellular carcinoma. Understanding the link between Wilson's disease and hepatocellular carcinoma will be beneficial for disease treatment and prevention.


Targeting vascular endothelial growth factor for relapsed and refractory adult acute myelogenous leukemias: therapy with sequential 1-beta-d-arabinofuranosylcytosine, mitoxantrone, and bevacizumab.
Vascular endothelial growth factor (VEGF) promotes acute myelogenous leukemia (AML) cell growth and survival and may contribute to drug resistance. bevacizumab, an anti-VEGF monoclonal antibody, exhibits clinical activity against diverse malignancies when administered with cytotoxic chemotherapy. We conducted a Phase II clinical trial of bevacizumab administered after chemotherapy to adults with refractory or relapsed AML, using a timed sequential therapy (TST) approach. bevacizumab 10 mg/kg was administered on day 8 after 1-beta-d-arabinofuranosylcytosine 2 g/m(2)/72 h beginning day 1 and mitoxantrone 40 mg/m(2) beginning day 4. In vivo laboratory correlates included AML cell VEGF receptor-1 (FLT-1) expression, marrow microvessel density, and free serum VEGF before and during TST with bevacizumab. Forty-eight adults received induction therapy. Myelosuppression occurred in all of the patients similar to other TST regimens. Toxicities were decreased ejection fraction (6%), cerebrovascular bleed (4%), and mortality of 15%. Overall response was 23 of 48 (48%), with complete response (CR) in 16 (33%). Eighteen (14 CR and 4 partial response) underwent one consolidation cycle and 5 (3 CR and 2 partial response) underwent allogeneic transplant. Median overall and disease-free survivals for CR patients were 16.2 months (64%, 1 year) and 7 months (35%, 1 year). Marrow blasts demonstrated FLT-1 staining before bevacizumab and marked decrease in microvessel density after bevacizumab. VEGF was detected in pretreatment serum in 67% of patients tested, increased by day 8 in 52%, and decreased in 93% (67% undetectable) 2 h after bevacizumab. In this single arm study, cytotoxic chemotherapy followed by bevacizumab yields a favorable CR rate and duration in adults with AML that is resistant to traditional treatment approaches. The clearance of marrow blasts in some patients after bevacizumab suggests that VEGF neutralization might result directly in leukemic cell death. The potential biological and clinical activity of bevacizumab in AML warrants additional clinical and laboratory study.


Biomarker Development for Intraductal Papillary Mucinous Neoplasms Using Multiple Reaction Monitoring Mass Spectrometry.
Intraductal papillary mucinous neoplasm (IPMN) is a common precursor of pancreatic cancer (PC). Much clinical attention has been directed toward IPMNs due to the increase in the prevalence of PC. The diagnosis of IPMN depends primarily on a radiological examination, but the diagnostic accuracy of this tool is not satisfactory, necessitating the development of accurate diagnostic biomarkers for IPMN to prevent PC. Recently, high-throughput targeted proteomic quantification methods have accelerated the discovery of biomarkers, rendering them powerful platforms for the evolution of IPMN diagnostic biomarkers. In this study, a robust multiple reaction monitoring (MRM) pipeline was applied to discovery and verify IPMN biomarker candidates in a large cohort of plasma samples. Through highly reproducible MRM assays and a stringent statistical analysis, 11 proteins were selected as IPMN marker candidates with high confidence in 184 plasma samples, comprising a training (n = 84) and test set (n = 100). To improve the discriminatory power, we constructed a six-protein panel by combining marker candidates. The multimarker panel had high discriminatory power in distinguishing between IPMN and controls, including other benign diseases. Consequently, the diagnostic accuracy of IPMN can be improved dramatically with this novel plasma-based panel in combination with a radiological examination.


The UK Pancreas Allocation Scheme for Whole Organ and Islet Transplantation.
In order to develop a national allocation scheme for donor pancreases, factors affecting waiting time and transplant outcomes in the United States (US) and United Kingdom (UK) were analyzed and compared. Blood group, sensitization, dialysis requirement, and whether the patient was waiting for a kidney and pancreas or pancreas alone affected waiting time in both countries; ethnicity and body mass index (BMI) also affected waiting time in the US. Ninety-day pancreas survival was similar in the UK and US, and was poorer for patients receiving a pancreas alone, with older donors, higher BMI and longer duration of ischemia in both countries. Factors affecting outcome, together with published data on factors affecting islet transplantation, informed the development of a points based allocation scheme for deceased donor pancreases in the UK providing equitable access for both whole organ and islet recipients through a single waiting list. Analysis of the allocation scheme 3 years after its introduction in December 2010 showed that the results were broadly as simulated, with a significant reduction in the number of long waiting patients and an increase in the number of islet transplants. There remains a surplus of highly sensitized patients in the waiting list, which the scheme should address in time.


Imperceptible somatosensory stimulation alters sensorimotor background rhythm and connectivity.
Most sensory input to our body is not consciously perceived. Nevertheless, it may reach the cortex and influence our behavior. In this study, we investigated noninvasive neural signatures of unconscious cortical stimulus processing to understand mechanisms, which (1) prevent low-intensity somatosensory stimuli from getting access to conscious experience and which (2) can explain the associated impediment of conscious perception for additional stimuli. Stimulation of digit 2 in humans far below the detection threshold elicited a cortical evoked potential (P1) at 60 ms, but no further somatosensory evoked potential components. No event-related desynchronization was detected; rather, there was a transient synchronization in the alpha frequency range. Using the same stimulation during fMRI, a reduced centrality of contralateral primary somatosensory cortex (SI) was found, which appeared to be mainly driven by reduced functional connectivity to frontoparietal areas. We conclude that after subthreshold stimulation the (excitatory) feedforward sweep of bottom-up processing terminates in SI preventing access to conscious experience. We speculate that this interruption is due to a predominance of inhibitory processing in SI. The increase in alpha activity and the disconnection of SI from frontoparietal areas are likely correlates of an elevated perception threshold and may thus serve as a gating mechanism for the access to conscious experience.


Allosteric modulation of β-arrestin-biased angiotensin II type 1 receptor signaling by membrane stretch.
It has recently been appreciated that the angiotensin II type 1 receptor (AT1R), a prototypic member of the G protein-coupled receptor superfamily, also functions as a mechanosensor. Specifically, mechanical stretch activates the AT1R to promote downstream signaling mediated exclusively by the multifunctional scaffold protein, β-arrestin, in a manner consistent with previously identified β-arrestin-biased ligands. However, the ligand-independent mechanism by which mechanical stretch promotes β-arrestin-biased signaling remains unknown. Implicit in the concept of biased agonism (i.e. the ability of an agonist to activate a subset of receptor-mediated signaling pathways) is the notion that distinct active conformations of the receptor mediate differential activation of signaling pathways. Here we determined whether mechanical stretch stabilizes distinct β-arrestin-activating conformations of the AT1R by using β-arrestin2-biased agonists as conformational probes in pharmacological and biophysical assays. When tested at cells expressing the AT1R fused to β-arrestin (AT1R-β-arrestin2), we found that osmotic stretch increased the binding affinity and potency of the β-arrestin-biased agonist TRV120023, with no effect on the balanced agonist AngII. In addition, the effect of osmotic stretch on ERK activation was markedly augmented in cells expressing the AT1R-β-arrestin2 fusion compared with the wild type AT1R and completely blocked in cells expressing the AT1R-Gq fusion. Biophysical experiments with an intramolecular BRET β-arrestin2 biosensor revealed that osmotic stretch and TRV120023 activate AT1Rs to stabilize β-arrestin2 active conformations that differ from those stabilized by the AT1R activated by angiotensin II. Together, these data support a novel ligand-independent mechanism whereby mechanical stretch allosterically stabilizes specific β-arrestin-biased active conformations of the AT1R and has important implications for understanding pathophysiological AT1R signaling.


Asystole with convulsion following a subanesthetic dose of propofol plus fentanyl.
A case is presented in which asystole and convulsions occurred after an attempted induction of anaesthesia with propofol and fentanyl. The case suggests that a history of syncope may be associated with unusual susceptibility to the bradycardic effects of propofol.


A study of hepatitis A seropositivity in Dallas County, Texas, 1998 through 1999.
This paper provides background information on the epidemiology and a descriptive analysis of infection with hepatitis A virus in Dallas County, Texas, for 1998 and 1999. Reported cases were obtained from the Dallas County Health Department, and incidence rates per 100,000 population were calculated. Persons who tested seropositive for hepatitis A virus between January 1, 1998, and December 31, 1999, were included. Variables of interest included age, sex, race, and date of occurrence. The overall incidence rate of this infection in Dallas County for 1998 was 1.9 times higher than that of the United States; in 1999, the overall rate for Dallas County increased by more than 1.6 times. Rates were significantly higher among males, highest among Hispanics, and lowest among blacks for both years. Incidence rates among age groups varied between years by increasing in people 50 years and older from 1998 to 1999 as a result of a single cafeteria-related outbreak of 150 cases in March 1999. Infection with hepatitis A virus remains the most reported vaccine-preventable disease in the United States.


Local and global representations of velocity: transparency, opponency, and global direction perception.
Human subjects can perceive global motion or motions in displays containing diverse local motions, implying representation of velocity at multiple scales. The phenomena of flexible global direction judgments, and especially of motion transparency, also raise the issue of whether the representation of velocity at any one scale is single-valued or multi-valued. A new performance-based measure of transparency confirms that the visual system represents directional information for each component of a transparent display. However, results with the locally paired random-dot display introduced by Qian et al, show that representations of multiple velocities do not coexist at the finest spatial scale of motion analysis. Functionally distinct scales of motion processing may be associated with (i) local motion detectors which show a strong winner-take-all interaction; (ii) spatial integration of local signals to disambiguate velocity; (iii) selection of reliable velocity signals as proposed in the model of Nowlan and Sejnowski; (iv) object-based or surface-based representations that are not necessarily organised in a fixed spatial matrix. These possibilities are discussed in relation to the neurobiological organisation of the visual motion pathway.


Early Achievement of Blood Pressure Lowering and Hematoma Growth in Acute Intracerebral Hemorrhage: Stroke Acute Management with Urgent Risk-Factor Assessment and Improvement-Intracerebral Hemorrhage Study.
Previous studies have revealed that hematoma growth mainly occurs during the first 6 h after the onset of spontaneous intracerebral hemorrhage (ICH). Early lowering of blood pressure (BP) may be beneficial for preventing hematoma growth. However, relationships between timing of BP lowering and hematoma growth in ICH remain unclear. We investigated associations between timing of BP lowering and hematoma growth for ICH. The Stroke Acute Management with Urgent Risk-factor Assessment and Improvement (SAMURAI)-ICH Study was a multicenter, prospective, observational study investigating the safety and feasibility of early (within 3 h from onset) reduction of systolic BP (SBP) to < 160 mm Hg with intravenous nicardipine for acute hypertension in cases of spontaneous ICH. The present study was a post hoc analysis of the SAMURAI-ICH study. We examined relationships between time from onset, imaging, and initiation of treatment to target SBP achievement and hematoma growth (absolute growth ≥6 mL) in ICH patients. Target SBP achievement was defined as the time at which SBP first became < 160 mm Hg. Among 211 patients, hematoma growth was seen in 31 patients (14.7%). The time from imaging to target SBP and time from treatment to target SBP were significantly shorter in patients without hematoma growth than in those with (p = 0.043 and p = 0.032 respectively), whereas no significant difference was seen in time from onset to SBP < 160 mm Hg between groups (p = 0.177). Patients in the lower quartiles of time from imaging to target SBP and time from treatment to target SBP showed lower incidences of hematoma growth (p trend = 0.023 and 0.037 respectively). The lowest quartile of time from imaging to target SBP (< 38 min) was negatively associated with hematoma growth on multivariable logistic regression (OR 0.182; 95% CI 0.038-0.867; p = 0.032). Early achievement of target SBP < 160 mm Hg is associated with a lower risk of hematoma growth in ICH.


Zintl phases for thermoelectric devices.
By converting waste heat into electricity and improving the efficiency of refrigeration systems, thermoelectric devices could play a significant role in solving today's energy problems. Increasing the thermoelectric efficiency (as measured by the thermoelectric material's figure-of-merit, zT) is critical to the development of this technology. Complex Zintl phases, in particular, make ideal candidates for thermoelectric materials because the necessary "electron-crystal, phonon-glass" properties can be engineered with an understanding of the Zintl chemistry. A recent example is the discovery that Yb(14)MnSb(11), a transition metal Zintl compound, has twice the zT as the material currently in use at NASA. This perspective outlines a strategy to discover new high zT materials in Zintl phases, and presents results pointing towards the success of this approach.


Heme is a carbon monoxide receptor for large-conductance Ca2+-activated K+ channels.
Carbon monoxide (CO) is an endogenous paracrine and autocrine gaseous messenger that regulates physiological functions in a wide variety of tissues. CO induces vasodilation by activating arterial smooth muscle large-conductance Ca2+-activated potassium (BK(Ca)) channels. However, the mechanism by which CO activates BK(Ca) channels remains unclear. Here, we tested the hypothesis that CO activates BK(Ca) channels by binding to channel-bound heme, a BK(Ca) channel inhibitor, and altering the interaction between heme and the conserved heme-binding domain (HBD) of the channel alpha subunit C terminus. Data obtained using thin-layer chromatography, spectrophotometry, mass spectrometry (MS), and MS-MS indicate that CO modifies the binding of reduced heme to the alpha subunit HBD. In contrast, CO does not alter the interaction between the HBD and oxidized heme (hemin), to which CO cannot bind. Consistent with these findings, electrophysiological measurements of native and cloned (cbv) cerebral artery smooth muscle BK(Ca) channels show that CO reverses BK(Ca) channel inhibition by heme but not by hemin. Site-directed mutagenesis of the cbv HBD from CKACH to CKASR abolished both heme-induced channel inhibition and CO-induced activation. Furthermore, on binding CO, heme switches from being a channel inhibitor to an activator. These findings indicate that reduced heme is a functional CO receptor for BK(Ca) channels, introduce a unique mechanism by which CO regulates the activity of a target protein, and reveal a novel process by which a gaseous messenger regulates ion channel activity.


Thinning Can Reduce Losses in Carbon Use Efficiency and Carbon Stocks in Managed Forests Under Warmer Climate.
Forest carbon use efficiency (CUE, the ratio of net to gross primary productivity) represents the fraction of photosynthesis that is not used for plant respiration. Although important, it is often neglected in climate change impact analyses. Here we assess the potential impact of thinning on projected carbon cycle dynamics and implications for forest CUE and its components (i.e., gross and net primary productivity and plant respiration), as well as on forest biomass production. Using a detailed process-based forest ecosystem model forced by climate outputs of five Earth System Models under four representative climate scenarios, we investigate the sensitivity of the projected future changes in the autotrophic carbon budget of three representative European forests. We focus on changes in CUE and carbon stocks as a result of warming, rising atmospheric CO2 concentration, and forest thinning. Results show that autotrophic carbon sequestration decreases with forest development, and the decrease is faster with warming and in unthinned forests. This suggests that the combined impacts of climate change and changing CO2 concentrations lead the forests to grow faster, mature earlier, and also die younger. In addition, we show that under future climate conditions, forest thinning could mitigate the decrease in CUE, increase carbon allocation into more recalcitrant woody pools, and reduce physiological-climate-induced mortality risks. Altogether, our results show that thinning can improve the efficacy of forest-based mitigation strategies and should be carefully considered within a portfolio of mitigation options.


Uniting paradigms of connectivity in marine ecology.
The connectivity of marine organisms among habitat patches has been dominated by two independent paradigms with distinct conservation strategies. One paradigm is the dispersal of larvae on ocean currents, which suggests networks of marine reserves. The other is the demersal migration of animals from nursery to adult habitats, requiring the conservation of connected ecosystem corridors. Here, we suggest that a common driver, wave exposure, links larval and demersal connectivity across the seascape. To study the effect of linked connectivities on fish abundance at reefs, we parameterize a demographic model for The Bahamas seascape using maps of habitats, empirically forced models of wave exposure and spatially realistic three-dimensional hydrological models of larval dispersal. The integrated empirical-modeling approach enabled us to study linked connectivity on a scale not currently possible by purely empirical studies. We find sheltered environments not only provide greater nursery habitat for juvenile fish but larvae spawned on adjacent reefs have higher retention, thereby creating a synergistic increase in fish abundance. Uniting connectivity paradigms to consider all life stages simultaneously can help explain the evolution of nursery habitat use and simplifies conservation advice: Reserves in sheltered environments have desirable characteristics for biodiversity conservation and can support local fisheries through adult spillover.


Decreased membrane fluidity of erythrocytes and cultured vascular smooth muscle cells in spontaneously hypertensive rats: an electron spin resonance study.
1. Membrane fluidity of erythrocytes and cultured vascular smooth muscle cells was studied in spontaneously hypertensive rats (SHR; Okamoto and Aoki strains) by means of an electron spin resonance (e.s.r.) and a spin-label technique. 2. The values of outer hyperfine splitting (2T') and of the order parameter (S) determined from e.s.r. spectra for a fatty acid spin-label agent (5-nitroxy stearate) were significantly higher in erythrocytes of SHR (4 and 10-13 weeks of age) than in those of age-matched Wistar-Kyoto rats (WKY). This finding suggests that the membrane fluidity of erythrocytes might be decreased in SHR. 3. The fluidity of cultured vascular smooth muscle cells obtained from 10-13-week-old SHR was also reduced compared with that from WKY. 4. These results suggest that the decreased membrane fluidity might be a genetically determined abnormality of the cell membranes in SHR.


Remembering with and without awareness in a depressed mood: evidence of deficits in initiative.
We propose that depressive deficits in remembering are revealed in tasks that allow the spontaneous use of strategies; tasks that bypass or direct the use of strategies should not produce depressive deficits. College students received depressive- or neutral-mood inductions after answering questions worded to reflect homophones' less common meaning. After the inductions, subjects spelled old and new homophones and showed no effect of the depressive inductions on unaware memory for the old homophones. Subsequent tests of recognition did, however, reveal differences according to the induced mood or the presence of naturally occurring depression (in Experiment 3). The differences, evidence of nondepressed subjects' use of strategies, tended to disappear when all subjects were provided with strategies for spelling or recognition. The results indicate that depressives experience deficits in cognitive initiative. We review the literature on depressive memory from this perspective.


Third harmonic frequency generation by type-I critically phase-matched LiB3O5 crystal by means of optically active quartz crystal.
We present a method of third harmonic generation at 355 nm by frequency mixing of fundamental and second harmonic radiation of an ytterbium nanosecond pulsed all-fiber laser in a type-I phase-matched LiB(3)O(5) (LBO) crystal where originally orthogonal polarization planes of the fundamental and second harmonic beams are aligned by an optically active quartz crystal. 8 W of ultraviolet light at 355 nm were achieved with 40% conversion efficiency from 1064 nm radiation. The conversion efficiency obtained in a type-I phase-matched LBO THG crystal was 1.6 times higher than the one achieved in a type-II LBO crystal at similar experimental conditions. In comparison to half-wave plates traditionally used for polarization alignment the optically active quartz crystal has much lower temperature dependence and requires simpler optical alignment.


Electrolyzed-reduced water protects against oxidative damage to DNA, RNA, and protein.
The generation of reactive oxygen species is thought to cause extensive oxidative damage to various biomolecules such as DNA, RNA, and protein. In this study, the preventive, suppressive, and protective effects of in vitro supplementation with electrolyzed-reduced water on H2O2-induced DNA damage in human lymphocytes were examined using a comet assay. Pretreatment, cotreatment, and posttreatment with electrolyzed-reduced water enhanced human lymphocyte resistance to the DNA strand breaks induced by H2O2 in vitro. Moreover, electrolyzed-reduced water was much more effective than diethylpyrocarbonate-treated water in preventing total RNA degradation at 4 and 25 degrees C. In addition, electrolyzed-reduced water completely prevented the oxidative cleavage of horseradish peroxidase, as determined using sodium dodecyl sulfate-polyacrylamide gels. Enhancement of the antioxidant activity of ascorbic acid dissolved in electrolyzed-reduced water was about threefold that of ascorbic acid dissolved in nonelectrolyzed deionized water, as measured by a xanthine-xanthine oxidase superoxide scavenging assay system, suggesting an inhibitory effect of electrolyzedreduced water on the oxidation of ascorbic acid.


Mapping of heterologous expressed sequence tags as an alternative to microarrays for study of defense responses in plants.
Microarray technology helped to accumulate an immense pool of data on gene expression changes in response to different environmental factors. Yet, computer- generated gene profiling using expressed sequence tags (EST) represents a valuable alternative to microarrays, which allows efficient discovery of homologous sequences in evolutionarily different species and comparison of gene sets on the whole genome scale. In this study, we used publicly available EST database derived from different plant species infected with a variety of pathogens, to generate an expression profile of homologous genes involved in defense response of a model organism, Arabidopsis thaliana. EST-driven prediction identified 4,935 genes (16% of the total Arabidopsis genome) which, according to the origin of EST sets, were associated with defense responses in the reference genome. Profiles of defense-related genes, obtained by mapping of heterologous EST, represent putative Arabidopsis homologs of the corresponding species. Comparison of these profiles in pairs and locating common genes allowed estimating similarity between defense-related gene sets of different plant species. To experimentally support computer data, we arbitrarily selected a number of transcription factor genes (TF) detected by EST mapping. Their expression levels were examined by real-time polymerase chain reaction during infection with yellow strain of Cucumber mosaic virus, a compatible virus systemically infecting Arabidopsis. We observed that 65% of the designated TF were upregulated in accordance with the EST-generated profile. We demonstrated that heterologous EST mapping may be efficiently used to reveal genes involved in host defense responses to pathogens. Upregulated genes identified in this study substantially overlap with those previously obtained by microarrays.


Evolutionary Dynamic Multiobjective Optimization: Benchmarks and Algorithm Comparisons.
Dynamic multiobjective optimization (DMO) has received growing research interest in recent years since many real-world optimization problems appear to not only have multiple objectives that conflict with each other but also change over time. The time-varying characteristics of these DMO problems (DMOPs) pose new challenges to evolutionary algorithms. Considering the importance of a representative and diverse set of benchmark functions for DMO, in this paper, we propose a new benchmark generator that is able to tune a number of challenging characteristics, including mixed Pareto-optimal front (convexity-concavity), nonmonotonic and time-varying variable-linkages, mixed types of changes, and randomness in type change, which have rarely or not been considered or tested in the literature. A test suite of ten instances with different dynamic features is produced from the generator in this paper. Additionally, a few new performance measures are proposed to evaluate algorithms for DMOPs with different characteristics. Six representative multiobjective evolutionary algorithms from the literature are investigated based on the proposed DMO test suite and performance measures. The experimental results facilitate a better understanding of strengths and weaknesses of these compared algorithms for DMOPs.


Measurement of prostaglandin metabolites is useful in diagnosis of small bowel ulcerations.
We recently reported on a hereditary enteropathy associated with a gene encoding a prostaglandin transporter and referred to as chronic enteropathy associated with SLCO2A1 gene (CEAS). Crohn's disease (CD) is a major differential diagnosis of CEAS, because these diseases share some clinical features. Therefore, there is a need to develop a convenient screening test to distinguish CEAS from CD. To examine whether prostaglandin E major urinary metabolites (PGE-MUM) can serve as a biomarker to distinguish CEAS from CD. This was a transactional study of 20 patients with CEAS and 98 patients with CD. CEAS was diagnosed by the confirmation of homozygous or compound heterozygous mutation of SLCO2A1. We measured the concentration of PGE-MUM in spot urine by radioimmunoassay, and the concentration was compared between the two groups of patients. We also determined the optimal cut-off value of PGE-MUM to distinguish CEAS from CD by receiver operating characteristic (ROC) curve analysis. Twenty Japanese patients with CEAS and 98 patients with CD were enrolled. PGE-MUM concentration in patients with CEAS was significantly higher than that in patients with CD (median 102.7 vs 27.9 μg/g × Cre, P < 0.0001). One log unit increase in PGE-MUM contributed to 7.3 increase in the likelihood for the diagnosis of CEAS [95% confidence interval (CI) 3.2-16.7]. A logistic regression analysis revealed that the association was significant even after adjusting confounding factors (adjusted odds ratio 29.6, 95%CI 4.7-185.7). ROC curve analysis revealed the optimal PGE-MUM cut-off value for the distinction of CEAS from CD to be 48.9 μg/g × Cre with 95.0% sensitivity and 79.6% specificity. PGE-MUM measurement is a convenient, non-invasive and useful test for the distinction of CEAS from CD.


Optimizing the robustness of electrical power systems against cascading failures.
Electrical power systems are one of the most important infrastructures that support our society. However, their vulnerabilities have raised great concern recently due to several large-scale blackouts around the world. In this paper, we investigate the robustness of power systems against cascading failures initiated by a random attack. This is done under a simple yet useful model based on global and equal redistribution of load upon failures. We provide a comprehensive understanding of system robustness under this model by (i) deriving an expression for the final system size as a function of the size of initial attacks; (ii) deriving the critical attack size after which system breaks down completely; (iii) showing that complete system breakdown takes place through a first-order (i.e., discontinuous) transition in terms of the attack size; and (iv) establishing the optimal load-capacity distribution that maximizes robustness. In particular, we show that robustness is maximized when the difference between the capacity and initial load is the same for all lines; i.e., when all lines have the same redundant space regardless of their initial load. This is in contrast with the intuitive and commonly used setting where capacity of a line is a fixed factor of its initial load.


The small molecule inhibitor anle145c thermodynamically traps human islet amyloid peptide in the form of non-cytotoxic oligomers.
Type 2 diabetes (T2DM) is associated with aggregation of the human islet amyloid polypeptide (hIAPP) into cytotoxic amyloid species. Here we tested the effect of a diphenylpyrazole (DPP)-derived small molecule inhibitor, anle145c, on cytotoxicity and on aggregation properties of hIAPP. We demonstrate that incubation of hIAPP with the inhibitor yields ~10 nm-sized non-toxic oligomers, independent of the initial aggregation state of hIAPP. This suggests that anle145c has a special mode of action in which anle145c-stabilized oligomers act as a thermodynamic sink for the preferred aggregation state of hIAPP and anle145c. We also demonstrate that the inhibitor acts in a very efficient manner, with sub-stoichiometric concentrations of anle145c being sufficient to (i) inhibit hIAPP-induced death of INS-1E cells, (ii) prevent hIAPP fibril formation in solution, and (iii) convert preformed hIAPP fibrils into non-toxic oligomers. Together, these results indicate that anle145c is a promising candidate for inhibition of amyloid formation in T2DM.


Accumulation of protein-bound 4-hydroxy-2-hexenal in spinal cords from patients with sporadic amyotrophic lateral sclerosis.
4-Hydroxy-2-hexenal (HHE) is a toxic, reactive aldehydic intermediate formed by nonenzymatic peroxidation of n-3 polyunsaturated fatty acids. The aim of this study was to determine the implication for HHE in the pathomechanism of amyotrophic lateral sclerosis (ALS) by immunohistochemical and enzyme-linked immunosorbent assay (ELISA) techniques using a mouse monoclonal IgG(1) antibody mAbHHE53 specific for protein-bound HHE. Immunohistochemical analysis on formalin-fixed, paraffin-embedded sections and frozen sections of spinal cords obtained at autopsy from 10 sporadic ALS patients and 10 age-matched control subjects demonstrated that protein-bound HHE immunoreactivity was seen and was prominent in the entire gray matter in the ALS cases and localized in the neurons, reactive astrocytes, microglial cells, and the surrounding neuropil, while the immunoreactivity was obscure or undetectable in the control cases. No significant protein-bound HHE immunoreactivity was seen in sections processed with omission of mAbHHE53 or in sections incubated with the antibody with an excess of the respective antigen. Competitive ELISA analysis on trypsin-digested protein extracts of fresh-frozen spinal cord samples disclosed a significant increase in protein-bound HHE level in the ALS cases compared with the control cases. Our results indicate that enhanced HHE formation occurs in the entire gray matter of sporadic ALS spinal cords and suggest that the selective vulnerability of motor neurons to HHE mediates the pathomechanism of this disease.


Data from the Human Penguin Project, a cross-national dataset testing social thermoregulation principles.
In the Human Penguin Project (N = 1755), 15 research groups from 12 countries collected body temperature, demographic variables, social network indices, seven widely-used psychological scales and two newly developed questionnaires (the Social Thermoregulation and Risk Avoidance Questionnaire (STRAQ-1) and the Kama Muta Frequency Scale (KAMF)). They were collected to investigate the relationship between environmental factors (e.g., geographical, climate etc.) and human behaviors, which is a long-standing inquiry in the scientific community. More specifically, the present project was designed to test principles surrounding the idea of social thermoregulation, which posits that social networks help people to regulate their core body temperature. The results showed that all scales in the current project have sufficient to good psychometrical properties. Unlike previous crowdsourced projects, this dataset includes not only the cleaned raw data but also all the validation of questionnaires in 9 different languages, thus providing a valuable resource for psychological scientists who are interested in cross-national, environment-human interaction studies.


Subnanometer-Diameter Wires Isolated in a Polymer Matrix by Fast Polymerization
The preparation and analysis of inorganic-organic polymer nanocomposites consisting of inorganic nanowires and multiwire "cables" in a random-coil organic polymer host is reported. Dissolution of inorganic (LiMo3Se3)n wires in a strongly coordinating monomer, vinylene carbonate, and the use of a rapid polymerization in the presence of a cross-linking agent produce nanocomposites without phase separation. Polymerization of dilute solutions yields a material containing mostly (Mo3Se3(-))n mono- and biwires, 6 to 20 angstroms in diameter and 50 to 100 nanometers long. Polymerization of more concentrated liquid crystalline solutions yields a nanocomposite containing oriented multiwire cables, 20 to 40 angstroms in diameter and up to 1500 nanometers long, that display optical anisotropy and electrical conductivity.


Bcl-2-mediated control of TRAIL-induced apoptotic response in the non-small lung cancer cell line NCI-H460 is effective at late caspase processing steps.
Dysregulation of the mitochondrial signaling pathway of apoptosis induction represents a major hurdle in tumor therapy. The objective of the presented work was to investigate the role of the intrinsic (mitochondrial) apoptotic pathway in the non-small lung cancer cell line NCI-H460 upon induction of apoptosis using the highly bioactive TRAIL derivative Db-scTRAIL. NCI-H460 cells were TRAIL sensitive but an only about 3 fold overexpression of Bcl-2 was sufficient to induce a highly TRAIL resistant phenotype, confirming that the mitochondrial pathway is crucial for TRAIL-induced apoptosis induction. TRAIL resistance was paralleled by a strong inhibition of caspase-8, -9 and -3 activities and blocked their full processing. Notably, especially the final cleavage steps of the initiator caspase-8 and the executioner caspase-3 were effectively blocked by Bcl-2 overexpression. Caspase-9 knockdown failed to protect NCI-H460 cells from TRAIL-induced cell death, suggesting a minor role of this initiator caspase in this apoptotic pathway. Rather, knockdown of the XIAP antagonist Smac resulted in enhanced caspase-3 degradation after stimulation of cells with TRAIL. Of note, downregulation of XIAP had only limited effects on TRAIL sensitivity of wild-type NCI-H460 cells, but resensitized Bcl-2 overexpressing cells for TRAIL-induced apoptosis. In particular, XIAP knockdown in combination with TRAIL allowed the final cleavage step of caspase-3 to generate the catalytically active p17 fragment, whose production was otherwise blocked in Bcl-2 overexpressing cells. Together, our data strongly suggest that XIAP-mediated inhibition of final caspase-3 processing is the last and major hurdle in TRAIL-induced apoptosis in NCI-H460 cells, which can be overcome by Smac in a Bcl-2 level dependent manner. Quantitative investigation of the XIAP/Smac interplay using a mathematical model approach corroborates our experimental data strengthening the suggested roles of XIAP and Smac as critical determinants for TRAIL sensitivity.


Food taboos in pregnancy and early lactation among women living in a rural area of West Bengal.
Pregnancy and lactation require greater need for nutrition for a mother but the situation becomes more complicated when a pregnant or a lactating woman follows or forced to undergo certain dietary restriction for the benefits of her baby. This study was conducted to know about the food taboos followed during pregnancy and early part of lactation by the women residing in a rural area. The study was conducted at different subcenters of Amdanga Community Development Block of North 24 Parganas district, West Bengal. The study was descriptive, observational with cross-sectional design, and was done through mixing of both quantitative and qualitative methods. Total four focus group discussions (FGDs) were conducted and 44 pregnant women and lactating mothers participated in those discussions. Notes and audio recording from FGDs were transcribed to written English language, analyzed, and principal domains were extracted. Taboos were present regarding consumption of various fruits (banana, papaya, jackfruit, coconut), vegetables (brinjal, leafy vegetables), meat, fish, and eggs during pregnancy. These were followed mainly to prevent miscarriage, promote easy delivery, and prevent fetal malformations. Taboos in the lactation included avoidance of small fish, foods with multiple seeds, other "cold" foods, and fluid restriction in some areas. The taboos were followed spontaneously as the inhibitions were imposed only for a definite period. Though diminished, food taboos are still prevalent in the rural areas of West Bengal. Nutrition education in pregnancy and lactation may be strengthened in those areas.


EMAS position statement: The ten point guide to the integral management of menopausal health.
With increased longevity and more women becoming centenarians, management of the menopause and postreproductive health is of growing importance as it has the potential to help promote health over several decades. Women have individual needs and the approach needs to be personalised. The position statement provides a short integral guide for all those involved in menopausal health. It covers diagnosis, screening for diseases in later life, treatment and follow-up.


Meta-analysis to test the association of HIV-1 nef amino acid differences and deletions with disease progression.
Previous relatively small studies have associated particular amino acid replacements and deletions in the HIV-1 nef gene with differences in the rate of HIV disease progression. We tested more rigorously whether particular nef amino acid differences and deletions are associated with HIV disease progression. Amino acid replacements and deletions in patients' consensus sequences were investigated for 153 progressor (P), 615 long-term nonprogressor (LTNP), and 2,311 unknown progressor sequences from 582 subtype B HIV-infected patients. LTNPs had more defective nefs (interrupted by frameshifts or stop codons), but on a per-patient basis there was no excess of LTNP patients with one or more defective nef sequences compared to the Ps (P = 0.47). The high frequency of amino acid replacement at residues S(8), V(10), I(11), A(15), V(85), V(133), N(157), S(163), V(168), D(174), R(178), E(182), and R(188) in LTNPs was also seen in permuted datasets, implying that these are simply rapidly evolving residues. Permutation testing revealed that residues showing the greatest excess over expectation (A(15), V(85), N(157), S(163), V(168), D(174), R(178), and R(188)) were not significant (P = 0.77). Exploratory analysis suggested a hypothetical excess of frameshifting in the regions (9)SVIG and (118)QGYF among LTNPs. The regions V(10) and (152)KVEEA of nef were commonly deleted in LTNPs. However, permutation testing indicated that none of the regions displayed significantly excessive deletion in LTNPs. In conclusion, meta-analysis of HIV-1 nef sequences provides no clear evidence of whether defective nef sequences or particular regions of the protein play a significant role in disease progression.


Proteomic profiling of the NCI-60 cancer cell lines using new high-density reverse-phase lysate microarrays.
Because most potential molecular markers and targets are proteins, proteomic profiling is expected to yield more direct answers to functional and pharmacological questions than does transcriptional profiling. To aid in such studies, we have developed a protocol for making reverse-phase protein lysate microarrays with larger numbers of spots than previously feasible. Our first application of these arrays was to profiling of the 60 human cancer cell lines (NCI-60) used by the National Cancer Institute to screen compounds for anticancer activity. Each glass slide microarray included 648 lysate spots representing the NCI-60 cell lines plus controls, each at 10 two-fold serial dilutions to provide a wide dynamic range. Mouse monoclonal antibodies and the catalyzed signal amplification system were used for immunoquantitation. The signal levels from the >30,000 data points for our first 52 antibodies were analyzed by using p-scan and a quantitative dose interpolation method. Clustered image maps revealed biologically interpretable patterns of protein expression. Among the principal early findings from these arrays were two promising pathological markers for distinguishing colon from ovarian adenocarcinomas. When we compared the patterns of protein expression with those we had obtained for the same genes at the mRNA level by using both cDNA and oligonucleotide arrays, a striking regularity appeared: cell-structure-related proteins almost invariably showed a high correlation between mRNA and protein levels across the NCI-60 cell lines, whereas non-cell-structure-related proteins showed poor correlation.


Science vs Fiction in Atomic Absorption.
The theoretical or experimental basis of some persistent statements in the literature on the general features of atomic absorption analysis is examined. The reputed advantages of atomic absorption over flame emission analysis, with respect to sensitivity and absence of excitation interference, are critically discussed, as well as the often over-estimated influence of resonance broadening on the shape of the analytical curve. Also, the curvature of the analytical curve with a continuum source is analyzed. The use of an auxiliary flame emitting a strongly self-absorbed metal line, as an effective continuum source, is suggested.


Multivalent gold nanoparticle-peptide conjugates for targeting intracellular bacterial infections.
Although nanoparticle-tagged antimicrobal peptides have gained considerable importance in recent years, their structure-function correlation has not yet been explored. Here, we have studied the mechanism of action of a designed antimicrobial peptide, VG16KRKP (VARGWKRKCPLFGKGG), delivered via gold nanoparticle tagging against Salmonella infection by combining biological experiments with high- and low-resolution spectroscopic techniques. In comparison with the free VG16KRKP peptide or gold nanoparticle alone, the conjugated variant, Au-VG16KRKP, is non-cytotoxic to eukaryotic cells, but exhibits strong bacteriolytic activity in culture. Au-VG16KRKP can penetrate host epithelial and macrophage cells as well as interact with intracellular S. Typhi LPS under both in vitro and in vivo conditions. Treatment of mice with Au-VG16KRKP post-infection with S. Typhi resulted in reduced intracellular bacterial recovery and highly enhanced protection against S. Typhi challenge. The three-dimensional high resolution structure of nanoparticle conjugated VG16KRKP depicted the generation of a well-separated amphipathic structure with slight aggregation, responsible for the increase of the local concentration of the peptide, thus leading to potent activity. This is the first report on the structural and functional characterization of a nanoparticle conjugated synthetic antimicrobial peptide that can kill intracellular pathogens and eventually protect against S. Typhi challenge in vivo.


Higher cardiorespiratory fitness attenuates arterial stiffening associated with the Ala54Thr polymorphism in FABP2.
Fatty acid binding protein 2 (FABP2) Ala54Thr polymorphism is a candidate gene associated with the risk of cardiovascular disease. Habitual exercise brings higher cardiorespiratory fitness and results in the improvement of cardiovascular disease risk. However, the effect of cardiorespiratory fitness level and FABP2 Ala54Thr polymorphism on the risk of cardiovascular diseases remains unclear. In the present study, a cross-sectional investigation of 837 Japanese men and women was performed to clarify the effects of cardiorespiratory fitness on the relationship between risk of cardiovascular disease and FABP2 Ala54Thr gene polymorphism. The study subjects were divided into high-cardiorespiratory fitness (High-Fit) and low-cardiorespiratory fitness (Low-Fit) groups based on the median value of peak oxygen uptake in each sex and decade. The FABP2 Ala54Thr polymorphism did not significantly affect carotid β-stiffness or blood pressure. In the Low-Fit group, carotid β-stiffness, systolic blood pressure, and diastolic blood pressure were higher for individuals with the Ala/Ala genotype compared with those with the Ala/Thr or Thr/Thr genotype, whereas no differences were observed in the High-Fit group. Additionally, serum triglyceride and plasma glucose levels were lower and serum high-density lipoprotein cholesterol levels were higher in the High-Fit group compared with the Low-Fit group; the FABP2 Ala54Thr polymorphism did not significantly affect these parameters. These results suggest that the higher cardiorespiratory fitness may attenuate the changes in central arterial stiffness and blood pressure that are associated with the FABP2 genotype.


Mate drinking and risk of lung cancer in males: a case-control study from Uruguay.
During the period from January 1988 to December 1994, a case-control study that included 497 cases of lung cancer and 497 controls was carried out at the Instituto de Oncologia, Montevideo, Uruguay, to evaluate the relationship between the drinking of mate (a local tea prepared with infusions of the herb Ilex paraguariensis) and the risk of lung cancer in men. Mate drinking has been associated with risk of most upper-aerodigestive tract cancers. After adjusting for major covariates, including pack-years of cigarette smoking, the amount of mate was associated with a 1.6-fold increase in risk for heavy drinkers, compared with light drinkers, with a significant dose-response pattern. When the analysis was performed by cell type, small cell lung cancer showed a significant increase in relative risk for mate amount (odds ratio, 2.9; 95% confidence interval, 1.3-6.2) and mate duration (odds ratio, 3.6; 95% confidence interval, 1.3-9.9). On the other hand, pulmonary adenocarcinoma was not associated with mate drinking. Possible reasons for these results are discussed, and areas for future research are suggested.


Needle oophoropexy: a new simple technique for ovarian transposition prior to pelvic irradiation.
Irradiation of the pelvis in the treatment of cancers will result in ovarian failure unless the ovaries are shielded adequately. To protect the ovaries, an oophoropexy may be performed. Our aim was to evaluate the feasibility, morbidity, and efficacy of laparoscopic ovarian transposition using a simple percutaneous needle technique. Fifteen patients (ten with rectal cancer and five with Hodgkin's disease) underwent the new laparoscopic oophoropexy technique. Laparoscopic releasing of the ovary was performed by cutting the utero-ovarian ligament followed by placing the ovaries on the anterior abdominal wall. A percutaneous straight needle was introduced through a 2-mm skin incision at the site of fixation. Repositioning of the ovaries was done on an outpatient basis without the need for readmission to the operating theatre. The technique was effective, reliable, and simple with no morbidities. Repositioning was performed simply in the outpatient clinic. At follow-up, 11 patients had evidence of ovarian function. Percutaneous needle transposition of the ovaries is a simple, effective, reliable, and easy-to-perform technique. It has short learning curve and can be done by less experienced laparoscopic surgeons.


A protocol of a cross-sectional study evaluating an online tool for early career peer reviewers assessing reports of randomised controlled trials.
Systematic reviews evaluating the impact of interventions to improve the quality of peer review for biomedical publications highlighted that interventions were limited and have little impact. This study aims to compare the accuracy of early career peer reviewers who use an innovative online tool to the usual peer reviewer process in evaluating the completeness of reporting and switched primary outcomes in completed reports. This is a cross-sectional study of individual two-arm parallel-group randomised controlled trials (RCTs) published in the BioMed Central series medical journals, BMJ, BMJ Open and Annals of Emergency Medicine and indexed with the publication type 'Randomised Controlled Trial'. First, we will develop an online tool and training module based (a) on the Consolidated Standards of Reporting Trials (CONSORT) 2010 checklist and the Explanation and Elaboration document that would be dedicated to junior peer reviewers for assessing the completeness of reporting of key items and (b) the Centre for Evidence-Based Medicine Outcome Monitoring Project process used to identify switched outcomes in completed reports of the primary results of RCTs when initially submitted. Then, we will compare the performance of early career peer reviewers who use the online tool to the usual peer review process in identifying inadequate reporting and switched outcomes in completed reports of RCTs at initial journal submission. The primary outcome will be the mean number of items accurately classified per manuscript. The secondary outcomes will be the mean number of items accurately classified per manuscript for the CONSORT items and the sensitivity, specificity and likelihood ratio to detect the item as adequately reported and to identify a switch in outcomes. We aim to include 120 RCTs and 120 early career peer reviewers. The research protocol was approved by the ethics committee of the INSERM Institutional Review Board (21 January 2016). The study is based on voluntary participation and informed written consent. NCT03119376.


Integration of EGA secure data access into Galaxy.
High-throughput molecular profiling techniques are routinely generating vast amounts of data for translational medicine studies. Secure access controlled systems are needed to manage, store, transfer and distribute these data due to its personally identifiable nature. The European Genome-phenome Archive (EGA) was created to facilitate access and management to long-term archival of bio-molecular data. Each data provider is responsible for ensuring a Data Access Committee is in place to grant access to data stored in the EGA. Moreover, the transfer of data during upload and download is encrypted. ELIXIR, a European research infrastructure for life-science data, initiated a project (2016 Human Data Implementation Study) to understand and document the ELIXIR requirements for secure management of controlled-access data. As part of this project, a full ecosystem was designed to connect archived raw experimental molecular profiling data with interpreted data and the computational workflows, using the CTMM Translational Research IT (CTMM-TraIT) infrastructure http://www.ctmm-trait.nl as an example. Here we present the first outcomes of this project, a framework to enable the download of EGA data to a Galaxy server in a secure way. Galaxy provides an intuitive user interface for molecular biologists and bioinformaticians to run and design data analysis workflows. More specifically, we developed a tool -- ega_download_streamer - that can download data securely from EGA into a Galaxy server, which can subsequently be further processed. This tool will allow a user within the browser to run an entire analysis containing sensitive data from EGA, and to make this analysis available for other researchers in a reproducible manner, as shown with a proof of concept study. The tool ega_download_streamer is available in the Galaxy tool shed: https://toolshed.g2.bx.psu.edu/view/yhoogstrate/ega_download_streamer.


Nutrient availability, the microbiome, and intestinal transport during pregnancy.
Adequate adaptation of the gastrointestinal tract is important during pregnancy to ensure that the increased metabolic demands by the developing fetus are met. These include changes in surface area mediated by villus hypertrophy and enhanced functional capacity of individual nutrient receptors, including those transporting glucose, fructose, leucine, and calcium. These processes are regulated either by the enhanced nutrient demand or are facilitated by changes in the secretion of pregnancy hormones. Our review also covers recent research into the microbiome, and how pregnancy could lead to microbial adaptations, which are beneficial to the mother, yet are also similar to those seen in the metabolic syndrome. The potential role of diet in modulating the microbiome during pregnancy, as well as the potential for the intestinal microbiota to induce pregnancy complications, are examined. Gaps in the current literature are highlighted, including those where only historical evidence is available, and we suggest areas that should be a priority for further research. In summary, although a significant degree of adaptation has been described, there are both well-established processes and more recent discoveries, such as changes within the maternal microbiome, that pose new questions as to how the gastrointestinal tract effectively adapts to pregnancy, especially in conjunction with maternal obesity.


Evaluation of cigarette smoke-induced emphysema in mice using quantitative micro-computed tomography.
Chronic cigarette smoke (CS) exposure provokes variable changes in the lungs, and emphysema is an important feature of chronic obstructive pulmonary disease. The usefulness of micro-computed tomography (CT) to assess emphysema in different mouse models has been investigated, but few studies evaluated the dynamic structural changes in a CS-induced emphysema mouse model. A novel micro-CT technique with respiratory and cardiac gating has resulted in high-quality images that enable processing for further quantitative and qualitative analyses. Adult female C57BL/6J mice were repeatedly exposed to mainstream CS, and micro-CT scans were performed at 0, 4, 12, and 20 wk. Emphysema was also histologically quantified at each time point. Air-exposed mice and mice treated with intratracheal elastase served as controls and comparisons, respectively. End-expiratory lung volume, corresponding to functional residual volume, was defined as the calculated volume at the phase of end-expiration, and it evaluated air trapping. The end-expiratory lung volumes of CS-exposed mice were significantly larger than those of air controls at 12 and 20 wk, which was in line with alveolar enlargement and destruction by histological quantification. However, CS exposure neither increased low attenuation volume nor decreased the average lung CT value at any time point, unlike the elastase-instilled emphysema model. CS-exposed mice had rather higher average lung CT values at 4 and 12 wk. This is the first study characterizing a CS-induced emphysema model on micro-CT over time in mice. Moreover, these findings extend our understanding of the distinct pathophysiology of CS-induced emphysema in mice.


Role of the parafusin orthologue, PRP1, in microneme exocytosis and cell invasion in Toxoplasma gondii.
The association of PRP1, a Paramecium parafusin orthologue, with Toxoplasma gondii micronemes, now confirmed by immunoelectron microscopy, has here been studied in relation to exocytosis and cell invasion. PRP1 becomes labelled in vivo by inorganic 32P and is dephosphorylated when ethanol is used to stimulate Ca2+-dependent exocytosis of the micronemes. The ethanol Ca2+-stimulated exocytosis is accompanied by translocation of PRP1 and microneme content protein (MIC3) from the apical end of the parasite. Immunoblotting showed that PRP1 is redistributed inside the parasite, while microneme content is secreted. To study whether similar changes occur during cell invasion, quantitative microscopy was performed during secretion, invasion and exit (egress) from the host cell. Time-course experiments showed that fluorescence intensities of PRP1 and MIC3 immediately after invasion were reduced 10-fold compared to preinvasion levels, indicating that PRP1 translocation and microneme secretion accompanies invasion. MIC3 regained fluorescence intensity and apical distribution after 15 min, while PRP1 recovered after 1 h. Intensity of both proteins then increased throughout the parasite division period until host cell lysis, suggesting the need to secrete microneme proteins to egress. These studies suggest that PRP1 associated with the secretory vesicle scaffold serves an important role in Ca2+-regulated exocytosis and cell invasion.


Polarization-dependent effects in point-by-point fiber Bragg gratings enable simple, linearly polarized fiber lasers.
Fiber Bragg gratings inscribed with a femtosecond laser using the point-by-point (PbP) technique have polarization dependent grating strength (PDGS) and exhibit birefringence. In this paper we quantify the dependence of these two properties on the ellipticity, position in the core and size of the micro-voids at the center of each refractive index modulation. We demonstrate that the effective modal index for type II gratings written with a femtosecond laser using the PbP method must be lower than that of the pristine fiber, and for the first time associate an axis with a polarization such that the long axis of the elliptically-shaped index modulations corresponds to the slow axis of the gratings. We exploit the PDGS of two gratings used as frequency-selective feedback elements as well as appropriate coiling, to realize a linearly-polarized fiber laser with a low birefringence fiber cavity. We show that the polarization-dependent grating strength is a function of the writing pulse energy and that only gratings optimized for this property will linearly polarize the fiber laser. The fiber lasers have high extinction ratios (>30 dB) for fiber lengths of up to 10 m and very stable polarized output powers (<0.5% amplitude fluctuations) in the range of 20-65 mW at 1540 nm. This method of polarization discrimination allows the realization of highly robust and simplified linearly polarized fiber lasers.


Quantitative Determination of Cross-Relaxation Rates in NMR Using Selective Pulses to Inhibit Spin Diffusion
Overhauser effects and hence internuclear distances can be measured accurately with selective experiments designed to suppress spin diffusion. It is essential to consider effects of both transverse and longitudinal relaxation during selective radiofrequency pulses. Fitting procedures allow one to refine selected cross-relaxation rate constants, and hence determine internuclear distances with improved accuracy. For the sake of illustration, selected cross-relaxation rates are determined that correspond to short- and long-range distances involving two diastereotopic sugar protons in a double-stranded B-DNA dodecamer. Such distances are difficult to distinguish by traditional Overhauser methods because of spin-diffusion effects.


School culture as an influencing factor on youth substance use.
To determine whether value-added education is associated with lower risk of substance use among adolescents: early initiation of alcohol use (regular monthly alcohol consumption in grade 7), heavy alcohol use (>10 units per week) and regular illicit drug use. Cross-sectional self-reported survey of alcohol and drug use. Analysis used two-level logistic modelling to relate schools providing value-added education with pupils' substance use. The value-added education measure was derived from educational and parenting theories proposing that schools providing appropriate support and control enhance pupil functioning. It was operationalised by comparing observed and expected examination success and truancy rates among schools. Expected examination success and truancy rates were based on schools' sociodemographic profiles. Data were collected across 15 West Midlands English school districts and included 25,789 pupils in grades 7, 9 and 11 from 166 UK secondary schools. Value-added education was associated with reduced risk of early alcohol initiation (OR (95% CI) 0.87 (0.78 to 0.95)) heavy alcohol consumption (OR 0.91 (0.85 to 0.96)) and illicit drug use (OR 0.90 (0.82 to 0.98)) after adjusting for gender, grade, ethnicity, housing tenure, eligibility for free school meal, drinking with parents and neighbourhood deprivation. The prevalence of substance use in school is influenced by the school culture. Understanding the mechanism through which the school can add value to the educational experience of pupils may lead to effective prevention programmes.


Simple, Scalable Proteomic Imaging for High-Dimensional Profiling of Intact Systems.
Combined measurement of diverse molecular and anatomical traits that span multiple levels remains a major challenge in biology. Here, we introduce a simple method that enables proteomic imaging for scalable, integrated, high-dimensional phenotyping of both animal tissues and human clinical samples. This method, termed SWITCH, uniformly secures tissue architecture, native biomolecules, and antigenicity across an entire system by synchronizing the tissue preservation reaction. The heat- and chemical-resistant nature of the resulting framework permits multiple rounds (>20) of relabeling. We have performed 22 rounds of labeling of a single tissue with precise co-registration of multiple datasets. Furthermore, SWITCH synchronizes labeling reactions to improve probe penetration depth and uniformity of staining. With SWITCH, we performed combinatorial protein expression profiling of the human cortex and also interrogated the geometric structure of the fiber pathways in mouse brains. Such integrated high-dimensional information may accelerate our understanding of biological systems at multiple levels.


Trkb signaling in pericytes is required for cardiac microvessel stabilization.
Pericyte and vascular smooth muscle cell (SMC) recruitment to the developing vasculature is an important step in blood vessel maturation. Brain-derived neurotrophic factor (BDNF), expressed by endothelial cells, activates the receptor tyrosine kinase TrkB to stabilize the cardiac microvasculature in the perinatal period. However, the effects of the BDNF/TrkB signaling on pericytes/SMCs and the mechanisms downstream of TrkB that promote vessel maturation are unknown. To confirm the involvement of TrkB in vessel maturation, we evaluated TrkB deficient (trkb (-/-)) embryos and observed severe cardiac vascular abnormalities leading to lethality in late gestation to early prenatal life. Ultrastructural analysis demonstrates that trkb(-/-) embryos exhibit defects in endothelial cell integrity and perivascular edema. As TrkB is selectively expressed by pericytes and SMCs in the developing cardiac vasculature, we generated mice deficient in TrkB in these cells. Mice with TrkB deficiency in perivascular cells exhibit reduced pericyte/SMC coverage of the cardiac microvasculature, abnormal endothelial cell ultrastructure, and increased vascular permeability. To dissect biological actions and the signaling pathways downstream of TrkB in pericytes/SMCs, human umbilical SMCs were treated with BDNF. This induced membranous protrusions and cell migration, events dependent on myosin light chain phosphorylation. Moreover, inhibition of Rho GTPase and the Rho-associated protein kinase (ROCK) prevented membrane protrusion and myosin light chain phosphorylation in response to BDNF. These results suggest an important role for BDNF in regulating migration of TrkB-expressing pericytes/SMCs to promote cardiac blood vessel ensheathment and functional integrity during development.


An effectiveness analysis of healthcare systems using a systems theoretic approach.
The use of accreditation and quality measurement and reporting to improve healthcare quality and patient safety has been widespread across many countries. A review of the literature reveals no association between the accreditation system and the quality measurement and reporting systems, even when hospital compliance with these systems is satisfactory. Improvement of health care outcomes needs to be based on an appreciation of the whole system that contributes to those outcomes. The research literature currently lacks an appropriate analysis and is fragmented among activities. This paper aims to propose an integrated research model of these two systems and to demonstrate the usefulness of the resulting model for strategic research planning. To achieve these aims, a systematic integration of the healthcare accreditation and quality measurement/reporting systems is structured hierarchically. A holistic systems relationship model of the administration segment is developed to act as an investigation framework. A literature-based empirical study is used to validate the proposed relationships derived from the model. Australian experiences are used as evidence for the system effectiveness analysis and design base for an adaptive-control study proposal to show the usefulness of the system model for guiding strategic research. Three basic relationships were revealed and validated from the research literature. The systemic weaknesses of the accreditation system and quality measurement/reporting system from a system flow perspective were examined. The approach provides a system thinking structure to assist the design of quality improvement strategies. The proposed model discovers a fourth implicit relationship, a feedback between quality performance reporting components and choice of accreditation components that is likely to play an important role in health care outcomes. An example involving accreditation surveyors is developed that provides a systematic search for improving the impact of accreditation on quality of care and hence on the accreditation/performance correlation. There is clear value in developing a theoretical systems approach to achieving quality in health care. The introduction of the systematic surveyor-based search for improvements creates an adaptive-control system to optimize health care quality. It is hoped that these outcomes will stimulate further research in the development of strategic planning using systems theoretic approach for the improvement of quality in health care.


Optimising the analysis of transcript data using high density oligonucleotide arrays and genomic DNA-based probe selection.
Affymetrix GeneChip arrays are widely used for transcriptomic studies in a diverse range of species. Each gene is represented on a GeneChip array by a probe-set, consisting of up to 16 probe-pairs. Signal intensities across probe-pairs within a probe-set vary in part due to different physical hybridisation characteristics of individual probes with their target labelled transcripts. We have previously developed a technique to study the transcriptomes of heterologous species based on hybridising genomic DNA (gDNA) to a GeneChip array designed for a different species, and subsequently using only those probes with good homology. Here we have investigated the effects of hybridising homologous species gDNA to study the transcriptomes of species for which the arrays have been designed. Genomic DNA from Arabidopsis thaliana and rice (Oryza sativa) were hybridised to the Affymetrix Arabidopsis ATH1 and Rice Genome GeneChip arrays respectively. Probe selection based on gDNA hybridisation intensity increased the number of genes identified as significantly differentially expressed in two published studies of Arabidopsis development, and optimised the analysis of technical replicates obtained from pooled samples of RNA from rice. This mixed physical and bioinformatics approach can be used to optimise estimates of gene expression when using GeneChip arrays.


Tumor necrosis factor inhibits growth hormone-mediated gene expression in hepatocytes.
Growth hormone (GH) stimulates STAT5 phosphorylation by JAK2, which activates IGF-I and serine protease inhibitor 2.1 (Spi 2.1) transcription, whereas STAT5 dephosphorylation by protein tyrosine phosphatases (PTPs) terminates this signal. We hypothesized that the inhibitory effects of TNF on GH signaling and gene transcription were responsible for hepatic GH resistance. CWSV-1 hepatocytes were treated with TNF, pervanadate (a PTP inhibitor), or both, before GH stimulation. Total and tyrosine-phosphorylated JAK2, STAT5, ERK1/2, SHP-1 and SHP-2, IGF-I, and Spi 2.1 mRNA levels were measured. GH stimulated STAT5 and ERK1/2 phosphorylation, IGF-I, and Spi 2.1 mRNA expression. TNF attenuated JAK2/STAT5 and ERK1/2 phosphorylation and IGF-I and Spi 2.1 mRNA expression following GH stimulation. SHP-1 and SHP-2 protein levels were unaltered by TNF or GH, and the GH-induced increase in SHP-1 PTP activity was not further increased by TNF. In TNF-treated cells, pervanadate restored STAT5 and ERK1/2 phosphorylation to control levels following GH stimulation but did not restore IGF-I or Spi 2.1 mRNA induction. Cells transfected with a Spi 2.1 promoter-luciferase vector demonstrate a 50-fold induction in luciferase activity following GH stimulation or cotransfection with a constitutively active STAT5 vector. TNF prevented the induction of Spi 2.1 promoter activity by GH and the STAT5 construct. We conclude that TNF does not inhibit GH activity by inducing SHP-1 or -2 expression and that correction of GH signaling defects in TNF-treated cells by pervanadate does not restore GH-induced gene expression. The inhibitory effects of TNF on GH-mediated gene transcription appear independent of STAT5 activity and previously identified abnormalities in JAK2/STAT5 signaling.


Covalent fragment-based ligand screening approaches for identification of novel ubiquitin proteasome system modulators.
Ubiquitination is a key regulatory mechanism vital for maintenance of cellular homeostasis. Protein degradation is induced by E3 ligases via attachment of ubiquitin chains to substrates. Pharmacological exploitation of this phenomenon via targeted protein degradation (TPD) can be achieved with molecular glues or bifunctional molecules facilitating the formation of ternary complexes between an E3 ligase and a given protein of interest (POI), resulting in ubiquitination of the substrate and subsequent proteolysis by the proteasome. Recently, the development of novel covalent fragment screening approaches has enabled the identification of first-in-class ligands for E3 ligases and deubiquitinases revealing so far unexplored binding sites which highlights the potential of these methods to uncover and expand druggable space for new target classes.


Out of pocket cost comparison between Caucasian and minority breast cancer survivors in the Breast Cancer Education Intervention (BCEI).
The purpose of this article is to: (1) describe out of pocket (OOP) costs among minority and Caucasian participants in the BCEI, the Breast Cancer Education Intervention, a randomized clinical trial of psychoeducational quality of life interventions for breast cancer survivors (BCS); and (2) examine the OOP burden, as measured by the proportion of income spent OOP, between the two racial/ethnic groups. We examined baseline OOP costs reported by 261 early-stage I and II breast cancer survivors who participated in the BCEI trial. Data were collected using the Breast Cancer Finances Survey and the Breast Cancer Sociodemographic and Treatment Tool. OOP costs averaged $316 per month since diagnosis. Direct medical costs were $281, and direct non-medical were $66. There were no significant differences in total OOP costs or direct medical and non-medical OOP costs between minority and Caucasian BCS. Minority BCS with incomes of $40,000 or less spent a greater proportion of income in total OOP and direct medical OOP costs (31.4 and 27% for BCS with incomes ≤ $20,000; 19.5 and 18.8% for BCS with incomes $20,001-40,0000) compared to their Caucasian counterparts (12.6 and 9.2% for BCS with incomes ≤ $20,000; 8.7 and 8.2% for BCS with incomes $20,001-40,0000). OOP costs can be a considerable burden for breast cancer survivors representing as much as 31% of monthly income depending on BCS' income levels. Future studies can investigate how this burden affects the quality of life of breast cancer survivors, especially minorities.


Review of tubulocystic carcinoma of the kidney with focus on clinical and pathobiological aspects.
Tubulocystic carcinoma of the kidney (TCK) is a recently established entity in renal neoplastic pathology. This review aims to give an overview of the clinical and pathobiological aspects of TCK. Grossly, the TCKs are well-demarcated multicystic lesions giving a "wrapped bubble" or "spongy" appearance. Microscopically, the tumors are composed of multiple, variably sized cysts separated by thin fibrous septa lacking ovarian stroma or desmoplastic reaction. The cysts are lined by tumor cells with eosinophilic cytoplasm and nuclear atypia of variable, but not infrequently of high grade corresponding to Fuhrman grade 3. A frequent association with papillary tumors has been reported. Recent molecular genetic studies of TCK have revealed distinct features separating this subset of renal cell carcinomas (RCCs) from other types of renal tumors including collecting duct carcinoma of Bellini and renal medullary carcinoma as well as pointing towards a close kinship with papillary RCC. Tubulocystic carcinoma of the kidney generally pursues an indolent clinical course. However, several cases with aggressive clinical behavior have been reported. We strongly feel that there is enough clinicopathological evidence to corroborate TCK as a separate entity and that it should be incorporated into the next WHO classification of renal tumors as a separate neoplastic category.


Chest Seal Placement for Penetrating Chest Wounds by Prehospital Ground Forces in Afghanistan.
Thoracic trauma represents 5% of all battlefield injuries. Communicating pneumothoraces resulting in tension physiology remain an important etiology of prehospital mortality. In addressing penetrating chest trauma, current Tactical Combat Casualty Care (TCCC) guidelines advocate the immediate placement of a vented chest seal device. Although the Committee on TCCC (CoTCCC) has approved numerous chest seal devices for battlefield use, few data exist regarding their use in a combat zone setting. To evaluate adherence to TCCC guidelines for chest seal placement among personnel deployed to Afghanistan. We obtained data from the Prehospital Trauma Registry (PHTR). Joint Trauma System personnel linked patients to the Department of Defense Trauma Registry, when available, for outcome data upon reaching a fixed facility. In the PHTR, we identified 62 patients with documented gunshot wound (GSW) or puncture wound trauma to the chest. The majority (74.2%; n = 46) of these were due to GSW, with the remainder either explosive-based puncture wounds (22.6%; n = 14) or a combination of GSW and explosive (3.2%; n = 2). Of the 62 casualties with documented GSW or puncture wounds, 46 (74.2%) underwent chest seal placement. Higher proportions of patients with medical officers in their chain of care underwent chest seal placement than those that did not (63.0% versus 37.0%). The majority of chest seals placed were not vented. Of patients with a GSW or puncture wound to the chest, 74.2% underwent chest seal placement. Most of the chest seals placed were not vented in accordance with guidelines, despite the guideline update midway through the study period. These data suggest the need to improve predeployment training on TCCC guidelines and matching of the Army logistical supply chain to the devices recommended by the CoTCCC.


Localization of cyclooxygenase-1 and -2 in adult and fetal human kidney: implication for renal function.
To gain insight into the roles of cyclooxygenase (COX)-1 and -2 in human kidney, we analyzed their expressions and localization in adult and fetal normal kidney. Immunohistology showed expression of COX-1 in collecting duct cells, interstitial cells, endothelial cells, and smooth muscle cells of pre- and postglomerular vessels. Expression of COX-2 immunoreactive protein could be localized to endothelial and smooth muscle cells of arteries and veins and intraglomerularly in podocytes. In contrast to the rat, COX isoforms were not detected in the macula densa. These data were confirmed by in situ mRNA analysis using digoxigenin-labeled riboprobes. In fetal kidney, COX-1 was primarily expressed in podocytes and collecting duct cells. Expression levels of COX-1 in both cell types increased markedly from subcapsular to juxtamedullary cortex. Glomerular staining of COX-2 was detectable in podocytes only at the endstage of renal development. In summary, the localization of COX-2 suggests that this enzyme may be primarily involved in the regulation of renal perfusion and glomerular hemodynamics. The expression of COX-1 in podocytes of the fetal kidney and its absence in adult glomeruli suggests that this isoform might be involved in glomerulogenesis.


Dopamine, oxytocin, and vasopressin receptor binding in the medial prefrontal cortex of monogamous and promiscuous voles.
Comparisons between monogamous and promiscuous vole species have proven useful in examining neurobiological mechanisms underlying social attachment. Reward processing is important for social attachment, and the medial prefrontal cortex (mPFC) exerts a direct influence on reward pathways. Dopamine (DA), oxytocin (OT), and arginine vasopressin (AVP) all have been implicated in the regulation of social attachment in monogamous voles. Therefore, we used radiolabeled ligands to examine dopamine D(1)- and D(2)-like, OT, and AVP V(1a) receptor binding densities in the mPFC of monogamous and promiscuous voles. Species differences were found; monogamous voles had higher densities of D(2)-like and OT receptor binding and lower densities of D(1)-like and V(1a) receptor binding than did promiscuous voles. Sex differences also were found; females had higher densities of OT receptor binding but lower densities of V(1a) receptor binding than did males in both species. Further, the laminar distribution of receptor binding indicates the possibility of an interaction between DA and OT systems in the mPFC in the regulation of social attachment. Differences in D(1)- and D(2)-like receptor binding between species are discussed in terms of how they might modulate cortical activity and subsequent DA release in the nucleus accumbens (NAcc).


Association between children's emotional/behavioral problems before adenotonsillectomy and postoperative pain scores at home.
Children undergoing adenotonsillectomy are at risk of severe postoperative pain and sleep problems. Little is known about the specific child risk factors for these problems. The aim of this study was to assess the occurrence of postoperative pain, sleep problems, and medication adherence, and assess the influence of internalizing and externalizing problems on postoperative pain. This prospective cohort study included 160 children, aged 1.5-5 years undergoing day-care adenotonsillectomy. Parents rated their child's pain with the Parents' Postoperative Pain Measure and their child's sleep problems with Vernon's Post Hospital Behavioral Questionnaire during the first 3 days and at day 10 postoperatively. Emotional/behavioral problems (ie, internalizing and externalizing behaviors) during the past 2 months were assessed using the Child Behavior Checklist. Regression analysis was used to assess whether children's pain intensity at home was associated with internalizing/externalizing problems, after controlling for age, preoperative child state anxiety, parental state anxiety, parental need for information, and socioeconomic status. Applying a threshold of ≥6 on the Parents' Postoperative Pain Measure, the incidence of moderate to severe pain was 57.6% at day 1, 53.5% at day 2, 35.4% at day 3, and 4.8% at day 10. During the first three postoperative nights, 37.1% of the children woke up. Internalizing problems (β = 0.343; P = 0.001) and parental need for information (β = 0.207; P = 0.011) were independently associated with higher pain scores at home during the first 3 days (R2 = 0.225). Following adenotonsillectomy, children often experienced moderate to severe pain and sleep problems during the first 3 days at home. Preoperative internalizing problems and parental need for information were independently associated with increased pain at home. Screening for these problems can help to identify vulnerable children and adapt the perioperative analgesic strategy accordingly (which includes preparation, information, and prescription of pain analgesics).


One-pot, modular approach to functionalized ketones via nucleophilic addition/Buchwald-Hartwig amination strategy.
A general one-pot procedure for the 1,2-addition of organolithium reagents to amides followed by the Buchwald-Hartwig amination with in situ released lithium amides is presented. In this work amides are used as masked ketones, revealed by the addition of organolithium reagents which generates a lithium amide, suitable for subsequent Buchwald-Hartwig coupling in the presence of a palladium catalyst. This methodology allows for rapid, efficient and atom economic synthesis of aminoarylketones in good yields.


Sensitivity evaluation of dynamic speckle activity measurements using clustering methods.
We evaluate and compare the use of competitive neural networks, self-organizing maps, the expectation-maximization algorithm, K-means, and fuzzy C-means techniques as partitional clustering methods, when the sensitivity of the activity measurement of dynamic speckle images needs to be improved. The temporal history of the acquired intensity generated by each pixel is analyzed in a wavelet decomposition framework, and it is shown that the mean energy of its corresponding wavelet coefficients provides a suited feature space for clustering purposes. The sensitivity obtained by using the evaluated clustering techniques is also compared with the well-known methods of Konishi-Fujii, weighted generalized differences, and wavelet entropy. The performance of the partitional clustering approach is evaluated using simulated dynamic speckle patterns and also experimental data.